Int J Cardiol. 2015 Mar 1;182:368-74. doi: 10.1016/j.ijcard.2014.12.005.

Quantification of Diastolic Dysfunction via the Age Dependence of Diastolic Function – impact of insulin resistance with and without type 2 diabetes

 

von Bibra H1, Paulus WJ2, St. John Sutton M3, Leclerque C1, Schuster T4, Schumm-Draeger PM1

1 Clinic for Endocrinology, Diabetes & Vascular Medicine, Klinikum Bogenhausen, Städt. Klinikum München GmbH, Munich, Germany

2 Institute for Cardiovascular Research Vrije Universiteit, VU University Medical Center Amsterdam, Amsterdam, the Netherlands

3 Department of Medicine, Cardiovascular Division, University of Pennsylvania, Philadelphia, PA, USA

4 Institute for Statistics and Epidemiology in Medicine of the Technische Universität, Munich, Germany

 

Abstract

Background: The alarming prevalence of heart failure with preserved ejection fraction requires quantification of diastolic dysfunction (DDF). Myocardial diastolic velocity E’ , as measured by tissue Doppler, implies age is the most important determinant. We tested the hypothesis that age allows for quantification of DDF and assessment of the structural and metabolic determinants in patients with and without type 2 diabetes (D).

Methods: This prospective, cross-sectional study assessed cardiovascular, metabolic and ultrasound data in 409 consecutive patients (Diabetes Center, Bogenhausen-Munich) between 20 and 90 years without known cardiac disease and either with (n=204) or without D but with common prevalence of cardiovascular risk factors, including a subgroup of healthy individuals (H, n=94).

Results: In H, E’ related to age as: E’norm = -0.163*years +19.69 (R2=0.77, p<0.0001). According to this 1% reduction by annual physiologic aging, DDF was quantitated as E’ – E’norm. Compared to non-diabetics, D patients were older, had greater BMI, lower E’, more cardiovascular risk and greater DDF. In non-diabetics, grading of DDF by E-E’norm correlated with grading by filling pressure E/E’. Determinants of DDF by multivariate analysis included pulse wave velocity, diastolic blood pressure and the triglyceride/HDL ratio (a marker of insulin resistance) in non-diabetics and in D the same risk factors in reverse sequence and heart rate. Neither left atrial size nor left ventricular mass had significant impact.

Conclusions: The physiological impact of age on myocardial function consists of a 1% annual reduction in E’ and enables precise quantification of diastolic dysfunction thereby unmasking the importance of metabolic risk for DDF.

KEYWORDS: Diastolic dysfunction; Heart failure preserved ejection fraction; Insulin resistance; Metabolic cardiomyopathy; Tissue Doppler; Type 2 diabetes

PMID: 25594925

 

 Supplementary

Heart failure is an ongoing epidemic of growing dimensions in western civilization due to the rising incidence of its predisposing risk factors age, diabetes and obesity. Approximately half of these patients have preserved systolic function and predominantly diastolic dysfunction. This entity is called heart failure with preserved ejection fraction (HFpEF). Unfortunately, the prognosis is as ominous as with systolic heart failure, but there is no known effective treatment [1].

This point creates great demand for respective research being the result of several problematic factors such as 1) incomplete understanding of the underlying pathophysiological mechanisms and 2) a lack of consensus how to define and to diagnose diastolic dysfunction by non-invasive techniques. The respective guideline recommendations are complex and have shown conflicting acceptance in clinical routine [2] and so did the respective main criterion, the non-invasively assessed left ventricular filling pressure E/E’ [3].

1) incomplete understanding of the underlying pathophysiological mechanisms:

In clinical terms, diastolic dysfunction is a functionally defined entity that is associated with diverse cardiovascular risk factors and comorbidities. Recent work has shown, that diastolic dysfunction is driven by a myocardial energy imbalance of demand and availability [4]. From the ischemic cascade it is well accepted knowledge, that an acute reduction of myocardial energy supply impairs diastolic function before systolic function – immediately, reversibly and without structural myocardial alterations. Accordingly we hypothesized, that the (dys-)regulation of energy availability is the key issue and cause for diastolic (dys-)function as suggested via biochemical mechanisms by Paulus and Tschöpe [5] so that the traditionally cited increases of left ventricular stiffness by structural modifications are rather consequences and remodeling processes, with the exception of primary myocardial disease such as hypertrophic cardiomyopathy. In epidemiological terms, energy imbalance and diastolic dysfunction are associated with risk factors and/or comorbidities such as age, obesity, diabetes, hypertension, ischemic heart disease, sleep apnea, chronic pulmonary disease, anemia, renal disease. Many of the underlying mechanisms relate to dysregulation of myocardial perfusion by microvascular endothelial inflammation and dysfunction [5] and to the harmful interaction of metabolic disease with intracardiocyte energy generation. Insulin resistance has a central role in these pathologic processes [6] but it has also the promising potential of therapeutic reversibility with subsequent improvement of diastolic function [7,8]. The importance of insulin resistance as risk has been unmasked in the present study by the quantification of diastolic dysfunction both in individuals with type 2 diabetes and also in individuals without diabetes but with a cardiovascular risk profile that is representative for the general population [9].

2) a lack of consensus how to define and to diagnose diastolic dysfunction by non-invasive techniques

The traditional echocardiographic assessment of diastolic and systolic left ventricular (LV) function by mitral inflow pattern and LV ejection fraction has been largely superceded by parameters derived from quantitative tissue Doppler imaging that measures maximal myocardial velocity E’ during early diastole in cm/s (and in analogy S’ during systole) (Fig 1) with high accuracy and feasibility at low costs. Furthermore, E’ sensitively mirrors dynamic changes of diastolic function in correlation to changes in exercise capacity and has been established as prognosticator for a long time. Yet, no functional criterion such as E’ has until now been identified as a reliable direct measure of active and energy consuming myocardial relaxation, possibly because in large cross-sectional studies, the strong age dependence of diastolic function implied a broad range of values thereby limiting the evaluation of diastolic dysfunction and its determinants.

 

HB FIG1

 

Indeed, the dominant influence of age on diastolic function leads to a 1% annual reduction as measured by tissue Doppler in healthy individuals (fig 2): E’ decreases linearly from 17 cm/s at the age of 20 years to 12 cm/s at 50 years and further on to 7 cm/s at the age of 80 years, that is altogether by 59% by physiologic ageing. The respective standardized regression coefficient ß is 0.88 and states that the impact of age as unchangeable predicting variable influences the dependent criterion E’ by 88% [9]. Mathematically, this strong age dependence requires that diastolic dysfunction is defined beyond this influence, in practical terms as comparison of the individually measured function E’ to the calculated value E’norm from the respective age based regression equation. Accordingly in the 405 study participants, diastolic dysfunction was designated if the deficit to E’norm was beyond the lower 95% confidence limit (fig 2). It was observed in 6% of the non-diabetic and in 28% of the diabetic individuals.

HB FIG2

 

With regards to the determinants of diastolic dysfunction, this quantitative approach unmasks the importance of metabolic risk, that is insulin resistance. Importantly also, it precludes the pseudo-identification of risk factors, that similarly depend on age as does diastolic dysfunction. Accordingly, myocardial wall thickness and left atrial size did not reach significance in the multivariate analysis for determinants of diastolic dysfunction. Instead, for non-diabetic individuals, significant impact factors were vascular stiffness (measured as pulse wave velocity), diastolic blood pressure and insulin resistance (measured as ratio triglycerides/high density lipoprotein cholesterol [10]), whereas in diabetic individuals, the same three impact factors appeared in reverse sequence, indicating that insulin resistance is the key issue.

In the management of diastolic dysfunction, the reference data E’norm is of clinical importance in several ways: 1) to evaluate without any influence from age the metabolic risk for myocardial function, in particular in individuals with insulin resistance and in the postmeal state, 2) to improve selection criteria and study objectives for therapeutic studies and 3) to differentiate patients with (preclinical) diastolic dysfunction for preventive management.

Collectively, the quantification of diastolic dysfunction via the age dependence of diastolic function identifies patients at risk for heart failure with preserved ejection fraction and unmasks the importance of metabolic risk, that is insulin resistance, for non-diabetic and for diabetic individuals.

 

Importance of the study: Our data suggest that treatment of insulin resistance by adequate nutrition and exercise and/or by pharmacologic therapy may exert important preventive and yet unexplored effects on cardiac dysfunction and that augmented microvascular endothelial function may represent a relevant compound to mediate improved control of myocardial energy supply and generation.

 

References

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  3. Tschöpe C, Paulus WJ (2009) Is echocardiographic evaluation of diastolic function useful in determining clinical care? – Doppler echocardiography yields dubious estimates of left ventricular diastolic pressure. Circulation 120:810-820
  4. Phan TT, Abozguia K, Shivu G et al (2009) Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol 54:4002-4009
  5. Paulus W, Tschöpe C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62:263-271
  6. Witteles RM, Fowler MB (2008) Insulin-resistant cardiomyopathy – clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol 51:93-102
  7. von Bibra H, St. John Sutton (2011) Impact of Diabetes on Postinfarction Heart Failure and Left Ventricular Remodeling. Current Heart Failure Reports 8:242-251
  8. von Bibra H, Wulf G, St John Sutton M et al (2014) A low- carbohydrate/high-protein diet improves diastolic cardiac function and the metabolic syndrome in overweight-obese patients with type 2 diabetes. IJC Metabolic & Endocrine 2:11-18
  9. von Bibra H, Paulus WJ, St John Sutton M et al (2015) Quantification of diastolic dysfunction via the age dependence of diastolic function –Impact of insulin resistance with and without type 2 diabetes. Int J Cardiol 182:368-374
  10. McLaughlin T, Reaven G, Abbasi Fet al (2005) Is There a Simple Way to Identify Insulin-Resistant Individuals at Increased Risk of Cardiovascular Disease? Am J Cardiol 96: 399-404

 

Contact:

Prof. Dr. Helene von Bibra

Clinic for Endocrinology, Diabetes & Vascular Medicine, Klinikum Bogenhausen, Munich

vonbibra@gmx.de

 

 

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